Protecting Against HPV: The Next Battleground?

Human papillomavirus (HPV) is many things to many people. As an infection of the skin, some varieties of HPV can cause annoying warts on the hands or feet, while other varieties of HPV infect the mucosa of the genitals and can cause warts -- or worse -- there.

There may be more than 100 kinds of HPV variants, with a few strongly linked to the development of cervical and anal cancer. Because the transmission of these worrisome kinds of HPV are associated with sex, the fight against the virus is becoming increasingly fraught with all of the fears, myths and misinformation that now accompanies any public health response to sexual issues in the United States. With two new vaccines against HPV on the horizon, there are emerging concerns that these weapons may not be effectively deployed due to moral and political objections. HPV infection is the most common sexually transmitted disease in the United States. Over 5 million cases are thought to occur each year, with half of all women between the ages 18 to 22 having vaginal infections at some point. The anal infection rate in young gay men is higher still. Infection occurs through skin-to-skin contact -- including areas not covered by condoms -- and warts need not be present for transmission to occur. Most infections are transient and are cleared by the immune system. Of the 40 or so types of HPV that infect the genital and anal regions, those that cause genital warts are deemed "low-risk" whereas those linked to cancer of the cervix or anus are termed "high risk." Types 16 and 18 are the most common high-risk varieties. Most HIV-negative people -- and 90 percent of women -- clear HPV infections within two years, but infections with types 16 and 18 seem to last longer. Studies have consistently found that persistent infection with varieties such as 16 and 18 are a necessary precondition for the development of precancerous lesions. Those who clear the virus are out of danger.

Although there is no treatment for chronic HPV infection, control of the associated anal and cervical cancers is fairly straightforward. Even so, there are about 5,000 U.S. deaths a year from such cancers and HPV infections may be more common and more difficult to treat in people with HIV.

Recently, the pharmaceutical manufacturers Merck and GlaxoSmithKline (GSK) each reported excellent results from preliminary trials of new vaccines against HPV. Merck expects to file for FDA marketing approval in the fall of 2005 and GSK in early 2006. Because of the ubiquity of the virus and the deadly consequence of infection in some people, a preventative vaccine for HPV could have significant public health benefits. Since active HPV infection may also increase the risk for acquiring HIV there has also been much speculation about the potential impact of these vaccines on HIV transmission rates.

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Abstinence Above All Else

In their battle to implement abstinence-until-marriage as official U.S. health policy, HPV has become a favorite cause of religious conservatives because of its cancer-causing potential, its widespread nature, and because it allows them to raise questions about the value of condoms in protecting against disease. These dangers are exaggerated because most HPV infections are largely transitory in nature, but facts have not been at the center of this campaign.

"Abstinence is the best way to prevent HPV ... Giving the HPV vaccine to young women could be potentially harmful, because they may see it as a license to engage in premarital sex," Bridget Maher, policy analyst for the Family Research Council (FRC) told New Scientist magazine this spring. Is it possible that an intervention as practical and necessary as a vaccine to prevent HPV could be derailed by such logic? Many fear that in the current political climate, it could.

Condoms as Protection

New studies presented this summer found that condom use does indeed correlate with protection against HPV. In the most strictly designed study yet of college women who were just beginning an active sexual life, self-reported 100 percent condom use resulted in a 70 percent reduction in genital HPV infections when compared with condom use in less than 5 percent of sexual encounters. Prior studies were more equivocal, and abstinence promoters like FRC frequently cite them. The older studies had severe limitations, however, as they included large numbers of women with past HPV infection. "Those studies did not cover the right population. It's hard to find women who haven't been infected by HPV already, and they weren't looking specifically at condoms," commented Laura Koutsky, the new study's senior author. Women with past exposure to HPV strains already have antibodies to protect them against those strains.

Reflecting Koutsky's concerns, another recent condom study looked at sexually experienced HIV-negative gay men and found that 60 percent had active HPV infections. In this study, those who always used condoms during receptive anal intercourse had one-third fewer new HPV infections than with those who used condoms less than 70 percent of the time.

The vaccine trials have run up against this same problem -- the universality of HPV -- when trying to gauge the vaccines' effect in men who have sex with men (MSM). Koutsky said, "You need to recruit never-infected gay men, but most MSM will already be infected so it's a hard study to do. Young gay men have many more sex partners than young women at the same age [and therefore more past HPV]. Limiting MSM to those with few sex partners would make it even harder to recruit."

Market Strategy Shapes the Vaccine

Merck's and GSK's responses to the technical and political challenges diverge considerably, and the contents of their vaccines -- even their names -- reflect the different positions.

GSK's vaccine, Cervarix, includes only HPV strains 16 and 18, which are responsible for 70 percent of cervical malignancies. The company plans to market the vaccine exclusively to women, as a cancer prevention agent. GSK claims that it would not be cost-effective to also vaccinate men and has conducted no studies with males or on anal cancer.

In an e-mail, GSK spokeswomen Amy Pollack told community groups, "Because cervical cancer takes many years to develop and remains asymptomatic for many years, it is easier to turn the question of introduction in girls into a hypothetical or political debate about adolescent sexuality. We will need your support in staying focused on drawing attention to and advocating for the real problem of cervical cancer."

Merck's version, Gardasil, includes HPV 6 and 11 in addition to 16 and 18. Strains 6 and 11 are implicated in 90 percent of genital warts. "The goal was, from a public health perspective, to protect against cancer and reduce the overall HPV health care burden," said Kelly Dougherty of Merck.

Both vaccines are three-dose affairs made up of noninfectious "virus-like particles," noninfectious synthetic shells made up of core protein from the targeted HPV strains. The GSK vaccine's main selling point is its proprietary adjuvant, "AS04," designed to trigger a quicker and stronger immune response. The response is said to be more durable, too, although the difference between an AS04-containing vaccine and one with the traditional aluminum salt adjuvant diminishes over time. In a phase II placebo-controlled trial, 721 women 15 to 25 years old completed the vaccine protocol. A significant reduction in new HPV 16/18 infections was seen in cervical and vaginal tissues (74% reduction compared to placebo after 27 months). In that period, the protection against persistent infection (at least six months duration) was 100 percent. GSK also recently reported evidence that its vaccine conferred 75 percent cross-protection against recurrent infection in several secondary oncogenic HPV types (31, 45 and 52). This would imply a possible further decline in overall cervical cancer rates among vaccine recipients.

Follow-up is continuing in the GSK phase II trial while four phase III trials have commenced. The phase III trials include a total of 36,000 women ranging from teenaged to 55 years old, with the vast majority 15 to 25.

Merck has reported similar compelling results for its quadrivalent vaccine. A phase II trial followed 478 women aged 16 to 23 for 36 months. The vaccine recipients' reduction of persistent infection was 89 percent overall compared with those who received the placebo. Protection against persistent HPV 16 was 86 percent; the vaccine conferred 89 percent protection against type 18. Merck has also reported that antibody response to the vaccine is stronger in 10 to 15 year-old males and females compared with 16 to 23 year-old females. There has always been an obvious need to vaccinate adolescents before they become sexually active, and these results strengthen the rationale for vaccinating younger individuals.

Merck has an ongoing study in 4,000 young men that contains an anal cancer endpoint as well as measuring heterosexual transmission. It is specifically including men who have sex with men. A study sponsored by the National Institutes of Health is evaluating response to the vaccine in preteen boys and girls infected with HIV. It provides an opportunity to evaluate its preventive potential in an HIV-positive cohort that has yet to be exposed to HPV. Overall, Merck's phase III trials have enrolled 25,000 persons, mostly young women. Women aged 25 to 45 have also been recruited in addition to young men. Later this year, Merck will go to the FDA with phase III data on efficacy in women (as judged by rates of persistent infection and advanced pre-cancerous lesions) plus immunogenicity (antibody response) in male and female adolescents.

More Than Cervical Cancer

A major compelling factor for the companies is that these vaccines promise to be marketing bonanza -- with each three-dose course expected to cost in the neighborhood of $300. Merck, for example, is planning to switch its old Vioxx sales network to Gardasil after FDA approval. Both companies will initially market the vaccines to young women.

Merck and GSK claim confidence that the FDA will recognize the medical consensus that vaccines will be a great help in controlling HPV-associated disease. Merck's Daugherty said, "We are confident that the regulatory agencies and everyone will want to use all the tools available to control HPV. Everyone we speak to is eager."

FDA approval is just the beginning to achieving broad public access. Guidelines from the Centers for Disease Control and Prevention (CDC) will determine which patients Medicaid and insurance companies will cover for this unprecedentedly expensive vaccine. A big battle may emerge over whether the guidelines ask schools to require the vaccine. This issue could be fought in community after community, where religious conservatives hold great sway.

The population most in need of the vaccine includes young people before sexual debut and those with high HIV risk. Gay and questioning teenagers are at the intersection of these criteria. Adolescents may not have the knowledge or means to obtain the vaccines on their own. Company preapproval presentations, meanwhile, already are replete with pictures of virginal, middle class young women. College students will certainly benefit from immunization, but the public health benefits will be greatly circumscribed if availability is limited to affluent adult women. Without help in obtaining access, the younger, less empowered teens could prove the weak link in eliminating HPV and its associated malignancies.

HPV by Itself and With HIV

Chronic HPV is, in principle, a manageable disease. Cellular changes can be monitored via cervical and anal Pap smears. Early-stage pre-cancerous and cancerous tumors can be excised before any malignancy has a chance to metastasize into the pelvic region, where they can prove disastrous. The United States, where regular cervical Pap screening is common, still records 14,000 cases of cervical cancer per year, including 4,000 deaths. For the world as a whole, there are nearly 300,000 cervical cancer deaths annually. Anal Pap smears are not usually preformed in the U.S. or elsewhere outside of a few medical practices that serve large numbers of gay men. The rate of anal cancer in gay men before the onset of the HIV epidemic is frequently compared with that of cervical cancer in women during the pre-Pap smear era. Yet because the U.S. gay male population is much smaller than that of all American women, the total anal cancer caseload is low compared to that of cervical cancer -- about 4,000 new cases in men and women and 700 deaths per year according to American Cancer Society estimates.

People with HIV have a considerably harder time eliminating HPV and a much higher prevalence of precancerous cervical and anal lesions (HSIL, or high-grade squamous epithelial lesions). A 1998 study found that persons with HIV had anal cancer rates 15 to 30 times that of the general population depending on the stage of HIV disease. There is even one report of HSIL in 18 percent of 117 HIV-positive men who denied ever engaging in receptive anal intercourse. By comparison, a recent study of HIV-negative MSM found a 5 percent rate of HSIL. Unfortunately, administration of antiretroviral therapy has proved to have at best modest effect on reversing pre-cancerous or cancerous lesions.

HPV is related to HIV transmission, too. It is widely thought that active infection -- and certainly the lesions associated with such infection -- makes people vulnerable to acquiring HIV. HPV also increases genital HIV levels, and this would be another way HPV promotes HIV transmission. Still, there are little hard data on the relationship between HPV and HIV acquisition. A new study to be presented at the 3rd International HIV Pathogenesis and Treatment Conference does indicate such a relationship. Joel Palefsky, the study's senior author notes, "I would say that the evidence is still very preliminary but strongly suggests the need for more work in this area. If confirmed, it would be very important indeed." The possibility of HIV transmission would be a major additional reason for male use of the HPV vaccine, even in the absence of specific studies.

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